Neoadjuvant radiochemotherapy (RCT) is now part of the armamentarium of cancer of the lower and middle rectum. It is recommended in current clinical practice prior to surgical excision if the lesion is classified T3/T4 or N+.
Trang 1S T U D Y P R O T O C O L Open Access
A multicentric randomized controlled trial on the impact of lengthening the interval between
neoadjuvant radiochemotherapy and surgery on complete pathological response in rectal cancer (GRECCAR-6 trial): rationale and design
Jérémie H Lefevre1,2*, Alexandra Rousseau3, Magali Svrcek2,4, Yann Parc1,2, Tabassome Simon2,3,
Emmanuel Tiret1,2and The French Research Group of Rectal Cancer Surgery (GRECCAR)
Abstract
Background: Neoadjuvant radiochemotherapy (RCT) is now part of the armamentarium of cancer of the lower and middle rectum It is recommended in current clinical practice prior to surgical excision if the lesion is classified T3/T4 or N+ Histological complete response, defined by the absence of persistent tumor cell invasion and lymph node (ypT0N0) after pathological examination of surgical specimen has been shown to be an independent
prognostic factor of overall survival and disease-free survival Surgical excision is usually performed between 6 and
8 weeks after completion of CRT and pathological complete response rate ranges around 12% In retrospective studies, a lengthening of the interval after RCT beyond 10 weeks was found as an independent factor increasing the rate of pathological complete response (between 26% and 31%), with a longer disease-free survival and
without increasing the operative morbidity The aim of the present study is to evaluate in 264 patients the rate of pathological complete response rate of rectal cancer after RCT by lengthening the time between RCT and surgery Methods/design: The current study is a multicenter randomized trial in two parallel groups comparing 7 and
11 weeks of delay between the end of RCT and cancer surgery of rectal tumors
At the end of the RCT, surgery is planified and randomization is performed after patient’s written consent for participation The histological complete response (ypT0N0) will be determined with analysis of the complete
residual tumor and double reading by two pathologists blinded of the group of inclusion Patients will be followed
in clinics for 5 years after surgery Participation in this trial does not change patient’s management in terms of treatment, investigations or visits Secondary endpoints will include overall and disease free survival, rate of
sphincter conservation and quality of mesorectal excision The number of patients needed is 264
Trial registration: ClinicalTrial.gov: NCT01648894
Keywords: Rectal cancer, Radiochemotherapy, Complete histological response, Procedure
* Correspondence: jeremie.lefevre@sat.aphp.fr
1
Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Digestive
Surgery, Hôpital Saint-Antoine, 184, rue du Fbg Saint-Antoine, 75012 Paris,
France
2 University Pierre & Marie Curie (UPMC-Paris 06), Paris, France
Full list of author information is available at the end of the article
© 2013 Lefevre et al.; licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
Trang 2Rectal cancer represents 12 000 new cases each year in
France [1] Its management is based on a
multidisciplin-ary management with radiotherapy, chemotherapy and
surgery
Surgery
Surgery consisting of total excision of the mesorectum
has improved over time The studies of Heald [2,3] have
showed that local recurrence rate was directly related to
the preservation of the fascia recti during the dissection
of the rectum In countries where this surgical procedure
was emphasized, the local recurrence rate and life
ex-pectancy after treatment of rectal cancer were improved
[4,5] In Sweden, after learning of the mesorectal
exci-sion technique, 447 patients were compared to older
co-horts, the local recurrence rate at 5 years was increased
from 20.5% to 8.2% and 5-year survival of 65.8% to
77.3% (p < 0.001 for both comparisons)
Radiotherapy
Before the widespread diffusion of the technique of
mesorectal excision, many studies, including 4 randomized
studies, had compared pre-operative radiotherapy (RT)
ver-sus surgery alone [6-9] Results showed only a benefit in
terms of local control with a reduction of 10% to 5% of the
recurrence rate local for patients with optimal dissection of
the mesorectum, but no survival benefit In 1997, a
ran-domized study in 1168 subjects showed an improved
sur-vival with neoadjuvant RT: sursur-vival at 9 years was 65% for
patients with no radiotherapy compared to 74% for patients
with neoadjuvant RT (p = 0.002) [9] Local recurrence for
patients treated by surgery alone was also more frequent
(27% (150/557) compared to 11% (63/553), p < 0.001) [9]
This finding was explained by a suboptimal surgical
resec-tion without complete mesorectum excision As a
conse-quence, an international randomized trial study comparing
RT + surgery versus surgery alone with quality control of
excision mesorectum [10] was conducted in 1805 patients
The results confirmed a higher rate of local control at
2 years in patients with preoperative radiotherapy (2.4%
vs 8.3%, p < 0.001), with no difference in terms of survival
(82% vs 81.8%, p = 0.84) Early postoperative
complica-tions were higher in the RT + surgery group (48% vs 41%,
p < 0.01) [11] After a minimum of 5 years of follow-up,
long-term complications; were more frequent in the
pre-operative radiotherapy group with (62% and 56% versus
38% and 33% of episodes of incontinence and pad wearing
respectively; p < 0.001) [12] As postoperative morbidity
and results functional obtained after preoperative RT were
very significantly altered, the authors recommended such
treatment only in patients at high risk of local recurrence
These recommendations were proposed by the French
experts for the treatment of rectal cancer and were ap-proved by the Haute Autorité de Santé in 2007 [13]
Chemoradiotherapy
Other studies have evaluated the impact of adding chemo-therapy to RT [14,15] The randomized trial of Bosset
et al included between 1993 and 2003, 1011 patients with rectal cancer T3 or T4 and analysed the impact of addition of chemotherapy based on 5-fluorouracil to RT 45Gy [14] compared with preoperative RT alone The complete response rate (pT0) on resected specimen was 5.3% in the RT alone group and 13.7% in the chemo-radiotherapy (CRT) group (odds ratio = 2.84, 95%CI: 1.75 to 4.59, p < 0.0001) [15] No benefit in overall sur-vival or disease-free sursur-vival was observed in CRT group despite a significant improvement rate of local recurrence
at 5 years (8.7% in the CRT compared to 17.1% after RT alone vs., p = 0.002) However, the results cannot be gener-alized because of the lack of uniform total mesorectal exci-sion for all patients included in this study
However, CRT has allowed the team of Pr Habr-Gama
to obtain a complete clinical regression of tumor rectal in 26.8% of cases (71/265 patients) [16] The protocol consisted of 50 Gy radiation therapy combined with chemotherapy based on 5-fluorouracil and leucovorin This group of patients had not been operated and simple surveillance without resection was performed After a mean follow-up of 57 months, only 2 patients (2.8%) had local recurrence and 3 had distant metastases The 5-year recurrence rate was 7% The complete clinical response was associated with better overall survival at 5 years: 100% versus 88% (p = 0.01)
In a retrospective series of the Cleveland Clinic, among 238 patients treated with neoadjuvant CRT, 58 (24.4%) had a ypT0N0 tumor on pathological exam Postoperative morbidity was similar in the neoadjuvant CRT group and in the no-pCR group, but there was a better local control (5 years local recurrence rate: 0% vs 10.6%, p < 0.001) [17]
Complete response: the importance of the period between the end of radiotherapy and surgery
The median complete response rate is about 12% [7-27%]
in the main series of rectal cancer treated with RT or RCT [18-31] A randomized study in 1999 had already found an effect in tumor reduction after RT between two intervals (2 weeks or 7 weeks) clinical response increased from 53.1% to 71.7% (p = 0.007) and pCR or near complete (persistence of some tumor cells) increased from 10.3% to 26% (p = 0.0054) [21] The results of this study cannot be generalized, considering the use of a technique of meso-rectal excision other than the widely distributed and ad-ministered neoadjuvant therapy (RT alone of 40 Gy) However the interest of extending the period after RT was
Trang 3obvious In 2003, Moore’s team showed that among 155
rectal cancers treated with neo-adjuvant RCT (50 Gy +
5-fluorouracil), the rate of complete response increased
from 9% to 23% between patients operated on before
the 40thday (between 6thand 7thweek) and those
oper-ated on after waiting more than 7 weeks (p = 0.09) [27]
Following the work of Prof Habr-Gama, other
au-thors have attempted to identify factors associated with
a pCR after surgical resection The first study published
by Tulchinsky et al [29] in 2008 reported the
retro-spective findings on the time between preoperative CRT
(45–50 Gy + 5-fluorouracil) and surgery (less or more
than 7 weeks) in 132 patients operated on by anterior
re-section or abdomino-perineal rere-section between 2000 et
2006 The rate of pCR or near complete (persistence of
microscopic foci of adenocarcinoma in the rectal wall
without lymph node) was 28% in the resected specimen
The single independent factor associated with a good
re-sponse was the period between the end of RT and surgery:
17% in the group operated <7 weeks against 35% in the
other group operated after 7 weeks (p = 0.03) There was
no association between the duration of interval before
sur-gery and postoperative morbidity (complications,
transfu-sion, duration of hospitalization) Kalady et al studied
retrospectively (1997–2007) records of 306 patients
oper-ated for a rectal cancer after CRT (50 Gy and
5-fluorouracil) [30] The dose of radiation received in each
group was similar The rate of pCR (ypT0N0) was 24% in
this study Time between the end of RCT and surgery, with
a cut-off estimated at 8 weeks was the single prognostic
factor for pCR in uni- and multivariate analysis (OR =
2.63-95%CI [1.13 to 6.12], p = 0.02) A The pathological
complete response rate increased from 16.3% (14/86) in
the group operated < 8 weeks against 30.8% (28/91) for
other (p = 0.03) The authors observed that the period
be-tween 8 and 10 weeks showed the greatest number of
complete responses and that there was no more gain over
14 weeks This retrospective study did not give any
explan-ation on the reasons for variexplan-ations in the time between the
end of radiotherapy and surgery [32] The group of patients
with pCR had a better overall survival with a follow-up of
60 months (91% versus 80%, p = 0.046) and less local
re-currence at 5 years (0% versus 11%, p = 0.023) A Korean
study analyzed retrospectively the data from 12 centers of
306 patients with a tumor classified ypT0 following CRT
This study confirmed the favourable impact of pCR after
neoadjuvant CRT on survival: the 5-year overall survival
of these patients having 93.4% of tumors initially classified
T3 or T4 was 92.8% Disease-free survival at 5 years was
84.6% Finally, Kalady et al compared the outcomes in a
retrospective series of 177 patients operated for a rectal
cancer after neoadjuvant treatment between patients
oper-ated before 8 weeks or after 8 weeks following the end of
CRT between 1997 and 2007 Postoperative morbidity or
mortality were similar between the two period group The rate of pCR was lower in the <8 weeks group compared with the > 8 weeks group (16.2% vs 31.1%, p = 0.027) Moreover, the 3 years local recurrence rate was significant lower in the >8 weeks (1.2% vs 3.9%, p = 0.04) [33] All these publications are retrospective and the real impact of the delay between the end of CRT and surgery
is still a matter of debate [34]
Aims
The main objective of our study is to evaluate in a ran-domized trial the impact of a longer interval between the end of CRT and rectal cancer surgery (7 weeks versus
11 weeks) on the rate of pathological complete response Secondary outcomes include overall and disease free sur-vival, quality of mesorectal excision, rate of sphincter preservation
Methods and design
This study is a multicenter randomized open-label con-trolled trial in parallel groups, comparing two periods be-tween the end of CRT and cancer surgery of rectal tumors: 7 weeks versus 11 weeks This study has been ap-proved by a national Institutional Review Board: the Re-gional Comity of Patients Protection of South-West I, N°1-12-19:30/08/12 and by the National Agency of Medi-cine and Medical Products (ANSM: B111580-10) This study is supported by a grant from the French Ministry of Health (PHRCN 2011, AOM 11314) The research carried out will be on accordance with Helsinki declaration
Participants
The institutional promoter is the AP-HP (Assistance Publique-Hôpitaux de Paris – DRCD: Département de la Recherche Clinique) Patients are included from several departments of surgery or oncology (n=26) in France (see list of participating centers in the Acknowledgments section) All participating sites signed a convention with the DRCD for ethical approval before beginning of inclu-sion All patients must fulfil the following criteria: T3/T4 and/or TxN + mid or low third rectal cancer and com-pleted RCT The complete inclusion and exclusion criteria are given in Table 1 After oral and written explanation about the purpose of this study, the patient gives his written consent agreeing to participate to the protocol (Figure 1)
Randomization
After completion of the pre-intervention assessments, the patients are randomly assigned to the period group (ratio 1:1) by Internet Blocked centralized randomisa-tion with stratificarandomisa-tion by centre will be prepared by URC-Est
Trang 4Surgical resection with total mesorectal excision (TME)
The anaesthesia consultation is planned before the
sur-gery according to the habits of each department
Partici-pation in the study does not alter the anaesthetic
procedures The patient is admitted the day before
sur-gery in the surgical ward
The type of resection (coloanal anastomosis,
abdomino-perineal resection, delayed anastomosis, drainage,
laparo-scopic approach…) is not influenced by the participation
to this protocol As the rectal tumor is located in the
mid-or low rectum a TME is required
Pathological exam
The pathological exam required has been already
pub-lished in the National French Guidelines [35] A
stan-dardized routine pathology examination was performed
using the protocol of Quirke et al [36] After fixation in
10% formalin and inking to assess the circumferential
margin, the whole tumor was cut transversely
Accor-ding to the macroscopical features, different techniques
for sampling of tumor tissues were applied in order to
avoid any under staging of the specimen:
– If there was only ulceration and fibrotic changes
without any visible tumoral lesion or if the tumor
residual measured less than 3 cm in diameter, the
lesion was examined entirely;
– If the residual tumor measured more than 3 cm in
diameter, one selected block per cm of tumor was
processed If the first selected blocks were free of tumor, complementary blocks were taken and the macroscopically residual lesion was examined in toto A diagnosis of pCR will only be made after examination of the whole macroscopically residual lesion [37] The tumor response is evaluated by inclusion of all residual tumor and the response to CRT is graded with the scales of Rodel and Dvorak [22,38] A double reading of slides will be made for each patient by two independent pathologists blinded to the randomization group of the patient to confirm the ypT stade as the two regression scores
In case of disagreement between the two pathologists, they should jointly give a mutual result
Outcomes and assessments Primary outcome
Rate of histological complete response after double read-ing by two different pathologist
Secondary outcomes
Mobidity, sphincter preservation rate, overall and disease-free survival
Surgical data
During surgery, the operating data are provided on the e-CRF (digital rectal examination under general anaesthesia, type of surgery (anterior resection or abdomino-perineal re-section), operative time, intraoperative bleeding, macroscopic
Table 1 Inclusion and exclusion criteria
• Performance status evaluated by the Eastern Cooperative Oncology
• rectal tumor with lower pole is more than 12 cm from the anal margin
or 10 cm from the dentate line,
• Patients with cancer of the middle or lower rectum (lesion located
within 10 cm from the dentate line or 12 cm from the anal margin)
proved by pathology,
• Patient did not complete the full protocol of radiotherapy,
• History of tumors (other than basal cell carcinoma and / or carcinoma in situ of the cervix)
• T3-T4N0, TxN+ on ultrasound-endoscopy and MRI, without secondary
localization (M0) on the thoraco-abdominal (or chest radiography and
abdominal ultrasound)
• A patient with impaired or incompetent
• investigator by not allowing him a good understanding of the requirements of the study, person under guardianship, persons under guardianship, persons deprived of their liberty by judicial or administrative body, adult subject to legal protection or unable to consent.
• Patient who received a protocol between 45–50 Gy of radiotherapy and
chemotherapy based on 5-fluorouracil for an average duration of 5 weeks
for the management of rectal cancer,
• Curative surgical treatment planned following radiochemotherapy with
total mesorectal excision,
• Free and informed consent signed by the patient,
• Patient affiliated to a social security scheme or beneficiary of such plan
(except AME)
• Patient able, according to the investigator, to comply with the
requirements of the study.
Trang 5appearance of the mesorectum, distance from the distal
limit of resection
Morbidity and mortality
The postoperative complications are noted by the
sur-geon in the e-CRF during hospitalization (about 10–
15 days) and during the first 3 months Postoperative
death is defined as death occurring within 30
postopera-tive days or during the first hospitalization Postoperapostopera-tive
complications are defined by the occurrence of medical
or surgical complications within 90 postoperative days
or during the first hospitalization Morbidity will be eval-uated with the new classification of surgical complica-tions by Dindo et al which includes 5 grades [39,40]
Pathological exam
Usual data are recorded: distal and circumferiential mar-gins, number of resected and invaded nodes, tumoral differenciation, presence of vascular embols (veinous or lymphatic, intra or extra-mural), perineural engainement, quality of mesorectal excision The resected specimen will
Figure 1 Flow chart.
Trang 6be staged according to American Joint Committee on
Cancer (AJCC) criteria (7thversion)
Rate of sphincter preservation
Comparison between the planned intervention at the
time of the randomisation and the resection performed
after peroperative digital exam will be performed
Oncological follow-up
Patients will be followed in clinics for 5 years according to
the habits of each department Usual follow-up is
com-posed of clinical exam, CEA analysis, CT-scan or Chest
Radiography with abdominal ultra-sound every 3–4 months
during the first three years and every 6 months for the last
two years
Samples size and statistical considerations
With a sample of 264 patients, GRECCAR6 trial has
80% of power to detect at least a two fold increase in the
complete response rate in the 11 weeks group compared
to the 7 weeks group This hypothesis assumes that the
complete response rate in the 7 weeks group is similar
to the usual rate of complete response after 6–8 weeks
(12% (Kalady et al Bosset et al Hiotis et al.)), with an
expected complete response rate in the 11 weeks group
of 26% and 10% of drop-outs, using a two-sided test at
the 0.05 significance level
Intention to treat analysis of the primary endpoint will
be performed once all randomized patients have
6 months of follow-up Analysis of survival will be
performed after at least 5 years of follow-up A futility
analysis [41] is planned after randomization after 132
pa-tients, using a Bayesian statistical interference, with no
impact on Type 1 error [42]
Discussion
While several retrospective studies has emphasised the
role of longer interval on efficiency of
radiochemother-apy on histological tumoral response, this multicentric
randomized trial is the first to evaluate this factor The
major drawback of previous studies is that no
explana-tions are given on the reasons for variaexplana-tions in the time
between the end of radiotherapy and surgery [29,32,43]
Indeed, the time interval was decided by the surgeon or
maybe in case of favourable clinical response, mainly
au-thors advocate other factors such as patient morbidity or
logistical scheduling issues [33]
This trial could then identify a simple and cheap factor
influencing the rate of pCR While is it still not obvious
that pCR is a good suggorate marker of the overall
sur-vival [44] based on previous randomized control trial on
CRT, it is probable that it could be a prognosis marker
of rectal conservation One publication showed that
patients operated after 8 weeks may have significantly less local recurrences
Indeed, if waiting 4 more weeks increase the rate of pCR, more patients could avoid a morbid surgical pro-cedure such as an abdomino-perineal resection This new management is still limited due to the actual diffi-culties to identify patients with pCR before surgery Adavances in radiological imaging may facilitate this im-portant point
Finally, this long delay would allow the use of chemo-therapy during this 3 months waiting period This could reduce the risk of synchronous metastasis that may occur during the waiting period
Competing interests The authors declare that they have no competing interests.
Authors ’ contributions JHL: conception of the study, writing of the manuscript AR: statistical analysis and help to draft the manuscript MS: pathological exam and help to draft the manuscript YP: writing of the manuscript TS: coordination of the study ET: conception and coordination of the study All authors read and approved the manuscript.
Acknowledgments
• Sponsor was « Assistance Publique – Hôpitaux de Paris ».
• The URC-est from Universitary Hospital of Paris Est for its logistic help.
• The study was funding by a grant from PHRCN 2011 (Ministère de la Santé) Thank you for adding this list of participating centers:
Participating centers:
1 Pr Yann Parc, Hôpital Saint-Antoine, Paris, yann.parc@sat.aphp.fr
2 Pr Yves Panis, Hôpital Beaujon, Clichy, yves.panis@bjn.aphp.fr
3 Pr Karoui Médhi, Hôpital Pitié Salpetrière, Paris, medhi.karoui@psl.aphp.fr
4 Pr Benoist Stéphane, Hôpital Bicêtre, Le Kremlin Bicêtre, stephane.benoist@bct.aphp.fr
5 Dr Loriau Jérôme, GH Saint Joseph, Paris, jloriau@gmail.com
6 Dr Pezet Denis, CHU Estaing, Clermont Ferrand, dpezet@chu.clermontferrand.fr
7 Pr Portier Guillaume, Hôpital Purpan, Toulouse, portier.g@chu-toulouse.fr
8 Dr De Chaisemartin Cécile, Institut Paoli-Calmette, Marseille, dechaisemartin@marseille.fnlcc.fr
9 Dr Jafari Mehrdad, Centre Oscar Lambret, Lille, m-jafari@o-lambret.fr
10 Pr Mariette Christophe, CHRU de Lille, christophe.mariette@chru-lille.fr
11 Pr Prudhomme Michel, GHU Carémeau, Nimes, michel.prudhomme@chu-nimes.fr
12 Pr Meunier Bernard, CHU Rennes, Rennes, bernard.meunier@chu-rennes.fr
13 Pr Tuech Jean Jacques, CHU Rouen, Rouen, jean-jacques.tuech@chu-rouen.fr
14 Dr Meurette Guillaume, Hôtel Dieu, CHU Nantes, guillaume.meurette@wanadoo.fr
15 Pr Rullier Eric, CHU Saint-André, Bordeaux, eric.rullier@chu-bordeaux.fr
16 Pr Dousset Bertrand, CHU Cochin, Paris, bertrand.dousset@cch.aphp.fr
17 Pr Berger Anne, Hôpital Georges Pompidou, Paris, anne.berger@egp.aphp.fr
18 Pr Pruvot François-René, CHRU de Lille, frpruvot@chru-lille.fr
19 Dr Eddy COTTE, CH Lyon Sud, eddy.cotte@chu-lyon.fr
20 Pr George MANTION, CHU Jean Minjoz, Besançon, georges.mantion@univ-fcomte.fr
21 Dr Laurent MINEUR, Institut Sainte Catherine, Avignon, l.mineur@isc84.org
22 Dr Jérôme DESRAME, Hôpital Privé Jean Mermoz, Lyon, jerome.desrame@orange.fr
23 Pr Christophe TRESALLET, Hôpital Pitie Salpêtriere, Paris, christophe.tresallet@psl.aphp.fr
24 Dr Nicolas GOASGUEN, Hôpital de la Croix Saint Simon, Paris, NGoasguen@hopital-dcss.org
25 Dr Laura BEYER, Hôpital Nord, Marseille, laura.beyer@ap-hm.fr
26 Dr Frédérique- Sophie PESCHAUD, Hôpital Ambroise Paré, Boulogne-Billancourt, frederique.peschaud@apr.aphp.fr
Trang 7Author details
1
Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Digestive
Surgery, Hôpital Saint-Antoine, 184, rue du Fbg Saint-Antoine, 75012 Paris,
France.2University Pierre & Marie Curie (UPMC-Paris 06), Paris, France.3AP-HP,
Clinical Research Unit (URC-Est), Department of Clinical Pharmacology,
Hôpital Saint-Antoine, Paris, France.4AP-HP, Departement of pathology,
Hôpital Saint-Antoine, Paris, France.
Received: 2 March 2013 Accepted: 9 September 2013
Published: 12 September 2013
References
1 Bouvier AM, Remontet L, Jougla E: Incidence of gastrointestinal cancers in
France Gastroenterol Clin Biol 2004, 28:877 –881.
2 Heald RJ, Ryall RD: Recurrence and survival after total mesorectal excision
for rectal cancer Lancet 1986, 1(8496):1479 –1482.
3 MacFarlane JK, Ryall RD, Heald RJ: Mesorectal excision for rectal cancer.
Lancet 1993, 341(8843):457 –460.
4 Martling A, Cedermark B, Johansson H, Rutqvist LE, Holm T: The surgeon as
a prognostic factor after the introduction of total mesorectal excision in
the treatment of rectal cancer Br J Surg 2002, 89(8):1008 –1013.
5 Martling A, Holm T, Rutqvist LE, Johansson H, Moran BJ, Heald RJ,
Cedermark B: Impact of a surgical training programme on rectal cancer
outcomes in Stockholm Br J Surg 2005, 92(2):225 –229.
6 Gerard A, Berrod JL, Pene F, Loygue J, Laugier A, Bruckner R, Camelot G,
Arnaud JP, Metzger U, Buyse M, et al: Preoperative radiotherapy and
radical surgery as combined treatment in rectal cancer Recent Results
Cancer Res 1988, 110:130 –133.
7 Stockholm Rectal Cancer Study Group: Preoperative short-term radiation
therapy in operable rectal carcinoma A prospective randomized trial.
Cancer 1990, 66(1):49 –55.
8 Randomised trial of surgery alone versus radiotherapy followed by
surgery for potentially operable locally advanced rectal cancer Medical
research council rectal cancer working party Lancet 1996,
348(9042):1605 –1610.
9 Improved survival with preoperative radiotherapy in resectable rectal
cancer Swedish rectal cancer trial N Engl J Med 1997, 336(14):980 –987.
10 Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T,
Rutten HJ, Pahlman L, Glimelius B, van Krieken JH, et al: Preoperative
radiotherapy combined with total mesorectal excision for resectable
rectal cancer N Engl J Med 2001, 345(9):638 –646.
11 Marijnen CA, Kapiteijn E, van de Velde CJ, Martijn H, Steup WH, Wiggers T,
Kranenbarg EK, Leer JW: Acute side effects and complications after
short-term preoperative radiotherapy combined with total mesorectal
excision in primary rectal cancer: report of a multicenter randomized
trial J Clin Oncol 2002, 20(3):817 –825.
12 Peeters KC, van de Velde CJ, Leer JW, Martijn H, Junggeburt JM, Kranenbarg EK,
Steup WH, Wiggers T, Rutten HJ, Marijnen CA: Late side effects of short-course
preoperative radiotherapy combined with total mesorectal excision for rectal
cancer: increased bowel dysfunction in irradiated patients –a Dutch colorectal
cancer group study J Clin Oncol 2005, 23(25):6199 –6206.
13 Portier G: [Recommendations for clinical practice Therapeutic choices for
rectal cancer How should neoadjuvant therapies be chosen?].
Gastroenterol Clin Biol 2007, 31 Spec No 1:23 –33.
14 Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A,
Bardet E, Beny A, Ollier JC: Chemotherapy with preoperative radiotherapy in
rectal cancer N Engl J Med 2006, 355(11):1114 –1123.
15 Bosset JF, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E,
Beny A, Briffaux A, Collette L: Enhanced tumorocidal effect of chemotherapy
with preoperative radiotherapy for rectal cancer: preliminary results –EORTC
22921 J Clin Oncol 2005, 23(24):5620 –5627.
16 Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U Jr, Silva e Sousa AH Jr,
Campos FG, Kiss DR, Gama-Rodrigues J Jr: Operative versus nonoperative
treatment for stage 0 distal rectal cancer following chemoradiation
therapy: long-term results Ann Surg 2004, 240(4):711 –717.
17 de Campos-Lobato LF, Stocchi L, da Luz MA, Geisler D, Dietz DW, Lavery IC,
Fazio VW, Kalady MF: Pathologic complete response after neoadjuvant
treatment for rectal cancer decreases distant recurrence and could
eradicate local recurrence Ann Surg Oncol 2011, 18(6):1590 –1598.
18 Medich D, McGinty J, Parda D, Karlovits S, Davis C, Caushaj P, Lembersky B:
advanced distal rectal adenocarcinoma: pathologic findings and clinical implications Dis Colon Rectum 2001, 44(8):1123 –1128.
19 Kim NK, Baik SH, Seong JS, Kim H, Roh JK, Lee KY, Sohn SK, Cho CH: Oncologic outcomes after neoadjuvant chemoradiation followed by curative resection with tumor-specific mesorectal excision for fixed locally advanced rectal cancer: impact of postirradiated pathologic downstaging on local recurrence and survival Ann Surg 2006, 244(6):1024 –1030.
20 Hiotis SP, Weber SM, Cohen AM, Minsky BD, Paty PB, Guillem JG, Wagman
R, Saltz LB, Wong WD: Assessing the predictive value of clinical complete response to neoadjuvant therapy for rectal cancer: an analysis of 488 patients J Am Coll Surg 2002, 194(2):131 –135 discussion 135–136.
21 Francois Y, Nemoz CJ, Baulieux J, Vignal J, Grandjean JP, Partensky C, Souquet JC, Adeleine P, Gerard JP: Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial J Clin Oncol 1999, 17(8):2396.
22 Rodel C, Martus P, Papadoupolos T, Fuzesi L, Klimpfinger M, Fietkau R, Liersch T, Hohenberger W, Raab R, Sauer R, et al: Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer J Clin Oncol 2005, 23(34):8688 –8696.
23 Gerard JP, Conroy T, Bonnetain F, Bouche O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, et al: Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203 J Clin Oncol 2006, 24(28):4620 –4625.
24 Stipa F, Chessin DB, Shia J, Paty PB, Weiser M, Temple LK, Minsky BD, Wong
WD, Guillem JG: A pathologic complete response of rectal cancer to preoperative combined-modality therapy results in improved oncological outcome compared with those who achieve no downstaging on the basis
of preoperative endorectal ultrasonography Ann Surg Oncol 2006, 13(8):1047 –1053.
25 Garcia-Aguilar J, Hernandez de Anda E, Sirivongs P, Lee SH, Madoff RD, Rothenberger DA: A pathologic complete response to preoperative chemoradiation is associated with lower local recurrence and improved survival in rectal cancer patients treated by mesorectal excision Dis Colon Rectum 2003, 46(3):298 –304.
26 Ruo L, Tickoo S, Klimstra DS, Minsky BD, Saltz L, Mazumdar M, Paty PB, Wong WD, Larson SM, Cohen AM, et al: Long-term prognostic significance
of extent of rectal cancer response to preoperative radiation and chemotherapy Ann Surg 2002, 236(1):75 –81.
27 Moore HG, Gittleman AE, Minsky BD, Wong D, Paty PB, Weiser M, Temple L, Saltz L, Shia J, Guillem JG: Rate of pathologic complete response with increased interval between preoperative combined modality therapy and rectal cancer resection Dis Colon Rectum 2004, 47(3):279 –286.
28 Stein DE, Mahmoud NN, Anne PR, Rose DG, Isenberg GA, Goldstein SD, Mitchell E, Fry RD: Longer time interval between completion of neoadjuvant chemoradiation and surgical resection does not improve downstaging of rectal carcinoma Dis Colon Rectum 2003, 46(4):448 –453.
29 Tulchinsky H, Shmueli E, Figer A, Klausner JM, Rabau M: An interval >7 weeks between neoadjuvant therapy and surgery improves pathologic complete response and disease-free survival in patients with locally advanced rectal cancer Ann Surg Oncol 2008, 15(10):2661 –2667.
30 Kalady MF, de Campos-Lobato LF, Stocchi L, Geisler DP, Dietz D, Lavery IC, Fazio VW: Predictive factors of pathologic complete response after neoadjuvant chemoradiation for rectal cancer Ann Surg 2009, 250(4):582 –589.
31 Lim SB, Choi HS, Jeong SY, Kim DY, Jung KH, Hong YS, Chang HJ, Park JG: Optimal surgery time after preoperative chemoradiotherapy for locally advanced rectal cancers Ann Surg 2008, 248(2):243 –251.
32 Yeo SG, Kim DY, Kim TH, Chang HJ, Oh JH, Park W, Choi DH, Nam H, Kim JS, Cho MJ, et al: Pathologic complete response of primary tumor following preoperative chemoradiotherapy for locally advanced rectal cancer: long-term outcomes and prognostic significance of pathologic nodal status (KROG 09 –01) Ann Surg 2010, 252(6):998–1004.
33 de Campos-Lobato LF, Geisler DP, da Luz MA, Stocchi L, Dietz D, Kalady MF: Neoadjuvant therapy for rectal cancer: the impact of longer interval between chemoradiation and surgery J Gastrointest Surg 2011, 15(3):444 –450.
34 Bujko K: Timing of surgery following preoperative therapy in rectal cancer: there is no need for a prospective randomized trial Dis Colon Rectum 2012, 55(3):31 –32.
35 Rullier A, Laurent C: [Recommendations for clinical practice Therapeutic
Trang 8excision of rectal cancer?] Gastroenterol Clin Biol 2007,
31 Spec No 1:34 –51 31S91-35.
36 Quirke P, Durdey P, Dixon MF, Williams NS: Local recurrence of rectal
adenocarcinoma due to inadequate surgical resection Histopathological
study of lateral tumour spread and surgical excision Lancet 1986,
2(8514):996 –999.
37 Tranchart H, Lefevre JH, Svrcek M, Flejou JF, Tiret E, Parc Y: What is the
incidence of metastatic lymph node involvement after significant
pathologic response of primary tumor following neoadjuvant treatment
for locally advanced rectal cancer? Ann Surg Oncol 2012, 20(5):1551 –1559.
38 Dworak O, Keilholz L, Hoffmann A: Pathological features of rectal cancer after
preoperative radiochemotherapy Int J Colorectal Dis 1997, 12(1):19 –23.
39 Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD,
de Santibanes E, Pekolj J, Slankamenac K, Bassi C, et al: The Clavien-Dindo
classification of surgical complications: five-year experience Ann Surg
2009, 250(2):187 –196.
40 Dindo D, Demartines N, Clavien PA: Classification of surgical
complications: a new proposal with evaluation in a cohort of 6336
patients and results of a survey Ann Surg 2004, 240(2):205 –213.
41 Armitage P: Interim analysis in clinical trials Stat Med 1991, 10(6):925 –935.
discussion 936 –927.
42 Kramar A, Mathoulin-Pelissier S: Methodes biostatistiques appliquées à la
recherche clinique en cancérologie Paris: John Libbey Eurotext; 2011.
43 Evans J, Tait D, Swift I, Pennert K, Tekkis P, Wotherspoon A, Chau I,
Cunningham D, Brown G: Timing of surgery following preoperative
therapy in rectal cancer: the need for a prospective randomized trial?
Dis Colon Rectum 2011, 54(10):1251 –1259.
44 Methy N, Bedenne L, Conroy T, Bouche O, Chapet O, Ducreux M, Gerard JP,
Bonnetain F: Surrogate end points for overall survival and local control in
neoadjuvant rectal cancer trials: statistical evaluation based on the FFCD
9203 trial Ann Oncol 2010, 21(3):518 –524.
doi:10.1186/1471-2407-13-417
Cite this article as: Lefevre et al.: A multicentric randomized controlled
trial on the impact of lengthening the interval between neoadjuvant
radiochemotherapy and surgery on complete pathological response in
rectal cancer (GRECCAR-6 trial): rationale and design BMC Cancer
2013 13:417.
Submit your next manuscript to BioMed Central and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at